Benefit of Alpelisib/Fulvestrant Combo in HR+/HER- Breast Cancer Confirmed With Biomarker Analysis


Combination of alpelisib and fulvestrant shows clinical benefit in patients with hormone receptor–positive, HER2-negative advanced breast cancer regardless of gene mutation status, according to a retrospective biomarker analysis.

Clinical benefit was demonstrated with alpelisib (Piqray) plus fulvestrant regardless of gene mutation status in patients with hormone receptor–positive, HER2-negative advanced breast cancer, according to a retrospective biomarker analysis of the phase 3 SOLAR-1 trial (NCT02437318).

Gene mutations include FGFR1 or FGFR2 alterations, according to findings presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

The planned exploratory biomarker analysis leveraged tumor samples collected at baseline (n = 398), which underwent next-generation sequencing using FoundationOne CDx 324-gene panel. Following sequencing of samples—80% of which were from primary tumors—the biomarker cohort for analysis included 237 patients with PI3KA-altered disease and 161 patients with PI3KA wild-type disease.

Data from the intention-to-treat population of the SOLAR-1 study served as the benchmark for the progression-free survival (PFS) analysis. The median PFS in the alpelisib plus fulvestrant arm was 11.0 months (95% CI, 7.5-14.5) compared with 5.7 months (95% CI, 3.7-7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50-0.85; P = .001).

Among patients with FGFR1 mutations the median PFS for those who received alpelisib plus fulvestrant (n = 22) was 12.7 months (95% CI, 5.3-22.1) compared with 3.8 months (95% CI, 1.6-5.6) for those who received placebo (n = 11; HR, 0.36; 95% CI, 0.16-0.77). The median PFS for those with FGFR2 mutations (9 patients in each arm) was 9.6 months (95% CI, 1.5-not available) with alpelisib vs 2.8 months (9%5 CI 1.4-29.9), respectively (HR, 0.28; 95% CI, 0.09-0.88).

FGFR1 was altered in 14% of patients with PI3KA-altered tumors and FGFR2 was altered in 8% of patients,” Dejan Juric, MD, said in a presentation of the data. [These data] are potentially important as FGFRalterations have been described as potential resistant mechanisms to endocrine therapy and/or CDK4/6 inhibitors. Here they do not seem to have an effect on alpelisib-based therapy.” Juric is the director of the Termeer Center for Targeted Therapies, program director of the Investigational Cancer Therapeutics Program at Massachusetts General Hospital, and an instructor in medicine at Harvard Medical School in Boston.

The randomized, double-blind, placebo-controlled SOLAR-1 trial evaluated the oral, α-specific PI3K wild-type and mutant inhibitor, alpelisib, plus fulvestrant vs placebo plus advanced or metastatic breast cancer whose disease had progressed or on or after receiving an aromatase inhibitor. The primary end point was investigator-assessed PFS in the cohort with PIK3CA-mutant disease.

Data from the primary analysis of SOLAR-1 supported the approval of alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor–positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.2

“Approximately 40% of patients with hormone receptor–positive, HER2-negative advanced breast cancer have activating mutations in PI3K contributing to endocrine therapy resistance and poor outcomes,” Juric said. “It should be noted that cooccurring alterations in upstream growth factor receptors, other regulators, or downstream effectors to PI3K may modulate the pathway output or affect the activity of alpelisib-directed therapy. We therefore focused our attention mapping out some of these effects.”

Overall, the investigators noted that genes were differentially altered in PIK3CA-altered and wild-type cohorts with observed differences in alteration frequency between the 2 cohorts. Specifically, those with PIK3CA-altered disease had a higher frequency of MAP3K1, TP53, FGFR2, EMSY, and CDH1.1

An analysis of patients by MYC mutation status, which signals resistance to PI3K inhibition, and RAD21expression, confirmed the limited benefit of alpelisib vs placebo. Among patients with PI3KA-altered disease, 12% had cooccurring MYC mutations and 18% had cooccurring RAD21 expression. The median PFS among 13 patients with MYC-mutant disease in the alpelisib cohort was 5.8 months (95% CI, 2.3-14.6) vs 6.4 months (95% CI, 1.8-14.8) in the placebo arm (n = 15; HR, 1.10; 95% CI, 0.45-2.28). Among those with RAD21 expression, the median PFS was 6.1 months (95% CI, 3.6-12.7) with alpelisib (n = 20) vs 7.2 months (95% CI, 1.9-14.8) with placebo (n = 23; HR, 1.02; 95% CI, 0.54-1.95).1

A trend toward clinical benefit was observed across gene alterations including among those with TP53mutations (HR, 0.49; 95% CI, 0.39-0.80); ESR1 mutations (HR, 0.70; 95% CI, 0.29-1.67); CCND1 (HR, 0.77; 95% CI, 0.29-1.67); MAP3K1 (HR, 0.44; 95% CI, 0.17-1.10); and ARID1A (HR, 0.50; 95% CI, 0.17-1.49). “I [want to] note that patients with MAP3K1 and/or ARD1A [mutations] who received alpelisib had a medium PFS of 17.3 and 22.1 months, respectively, which was approximately 10 months longer [than with placebo],” Juric said.

In addition to an analysis of patients with FGFR1/FGFR2 mutations, investigators conducted an analysis of genes implicated in CDK4/6 inhibitor resistance including PTEN, AURKA, NF1, ATM, ATR, RB1, CDK4, CDKN2A/B/C. The median PFS for those with CDK4/6-resistant alterations who received alpelisib plus fulvestrant (n = 33) was 7.7 months (95% CI, 5.3-14.6) vs 3.8 months (95% CI, 1.9-7.2) with placebo (n = 35; HR, 0.52; 95% CI, 0.30-0.89).1

In an analysis of tumor mutational burden (TMB) quartiles, the clinical benefit with alpelisib was consistent in those with high TMB and more pronounced among those with low TMB. Patients were stratified by TMB: quartile 1 (0-<2.52 mut/mb); quartile 2 (2.52-<3.78 mut/mb); quartile 3 (3.78-<5.04 mut/mb); and quartile 4 (≥ 5.04 mut/mb).

The median PFS for those in quartile 1 with TMB-low disease was 18.5 months (95%, 7.7-22.1) with alpelisib plus fulvestrant vs 3.2 months (95% CI, 1.8-7.4) with placebo (HR, 0.38; 95% CI, 0.21-0.68). In those with TMB-high disease in quartile 4, the median PFS was 7.4 months (95% CI, 5.5-17.3) vs 5.1 months (95% CI, 1.9-7.4), respectively (HR, 0.68; 95% CI, 0.40-1.17).

Juric concluded by cautioning that these data are hypothesis generating and will require further investigations.

1. Juric D, Rugo HS, Reising A, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): biomarker (BM) analyses by next-generation sequencing (NGS) from the SOLAR-1 study. J Clin Oncol. 2022;40(suppl 16):1006. doi:10.1200/JCO.2022.40.16_suppl.1006
2. FDA approves alpelisib for metastatic breast cancer. News release. FDA. Updated May 28, 2019. Accessed June 4, 2022.
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